Aging Symptom Trajectories in Mother Carriers of the FMR1 Premutation

项目摘要/摘要 在美国，大约每151名女性中就有一名携带一种名为FMR1前突变的基因异常 (FXPM)。携带FXPM的母亲有将突变基因遗传给孩子的风险，这可能会导致 患有脆性X综合征。FXPM还与显著增加的疾病风险有关，包括 神经退行性疾病，过早绝经，精神疾病，以及执行和社会缺陷。 新证据表明，FXPM携带者的母亲可能会经历与年龄相关的过早下降 多个症状域。FXPM表型的老化表达在应用时尤其令人担忧 因为这些症状不仅影响携带者母亲，而且还影响她 有能力照顾和支持患有脆性X综合征的孩子。然而，几乎所有的年代证据- 这一群体的相关下降是从横截面数据中收集的，这些数据不足以得出稳健的结论 纵向轨迹。这是有效临床管理的重大障碍，因为我们缺乏 需要数据来了解FXPM基因的长期影响及其对家庭的影响。 这项建议旨在确定关键FXPM表型(心理健康、高管、社交)的稳定性 FXPM携带者母亲的中年和老年早期与健康对照组的比较(目标1)；调查 与年龄相关症状表达相关的自主神经和分子遗传因素及其相互作用 有育儿压力(目标2)；评估与各年龄段FXPM症状相关的功能限制 (目标3)。我们将通过采用加速纵向设计来跟踪与年龄相关的数据，从而实现这些目标 与75名对照母亲相比，75名FXPM携带者母亲在45-80年间发生了变化。已经过去了- 主要目标是告知与年龄相关的下降的关键年龄段和风险因素，以及奠定 为今后的力学研究奠定基础。这项工作对于制定改进FXPM的策略是必要的 症状，这将改善FXPM携带者母亲及其患有脆性X的孩子的预后 综合症。

PROJECT SUMMARY/ABSTRACT About 1 in 151 women in the US are carriers of a genetic abnormality called the FMR1 premutation (FXpm). Mothers who carry the FXpm are at risk for passing the mutated gene to their children, which may result in fragile X syndrome. The FXpm is also associated with substantially increased risk for disease, including neurodegenerative disease, premature menopause, psychiatric involvement, and executive and social deficits. New evidence suggests that FXpm carrier mothers may experience premature age-related decline across multiple symptom domains. The aging expression of FXpm phenotype is particularly concerning when applied within the context of fragile X families because these symptoms impact not only the carrier mother, but also her ability to care and advocate for her children with fragile X syndrome. However, almost all evidence of age- related decline in this group has been gleaned from cross-sectional data that are insufficient for drawing robust longitudinal trajectories. This represents a substantial barrier to effective clinical management, as we lack the data needed to understand the long-term effects of the FXpm genotype and its implications for families. This proposal seeks to determine the stability of key FXpm phenotypes (mental health, executive, social) across midlife and early old age in FXpm carrier mothers compared to healthy controls (Aim 1); investigate autonomic and molecular-genetic factors associated with age-related symptom expression and their interface with parenting stress (Aim 2); and evaluate functional limitations associated with FXpm symptoms across age (Aim 3). We will accomplish these aims by adopting an accelerated longitudinal design to track age-related change occurring across 45-80 years in 75 FXpm carrier mothers compared to 75 control mothers. The over- arching goal is to inform the critical age periods and risk factors in age-related decline, as well as to lay the groundwork for future mechanistic studies. This work is necessary to develop strategies to ameliorate FXpm symptoms, which will improve outcomes for both FXpm carrier mothers and their children with fragile X syndrome.